Hepatitis C: Update in Clinical Managements3.gi.org/wp-content/uploads/2013/01/13ACG_Western... · Hepatitis C: Update in Clinical Management Bruce R. Bacon, ... Cor Aercan Coee o

Bruce R. Bacon, MD, FACG

Hepatitis C: Update in Clinical Management

Bruce R. Bacon, M.D.James F. King M.D. Endowed Chair in Gastroenterology

Professor of Internal MedicineDivision of Gastroenterology and Hepatology

S i t L i U i it Li C tSaint Louis University Liver CenterSaint Louis University School of Medicine

St. Louis, Missouri

Disclosure Slide

• Dr. Bacon has a financial relationship with Merck Kadmon Vertex Gilead AbbottMerck, Kadmon, Vertex, Gilead, Abbott, Roche/Genentech, ISIS, and Bristol-Myers Squibb.

ACG Regional Postgraduate Course - Los Angeles, CA Copyright 2013 American College of Gastroenterology

1


The Hepatitis Epidemic

• US prevalence of chronic hepatitis C

5 million exposed– 5 million exposed

– 3.5 million with chronic viremia

• Worldwide prevalence of chronic hepatitis C-170 million

• Most patients with hepatitis C are asymptomatic until irreversible liver damage occurs

• Diagnosis depends upon a high index of suspicion and proper screening

• New guidelines from CDC for screening

Why Treat Chronic Hepatitis C?• The disease

– Common, chronic, and potentially progressivep y p g– Complications are becoming more common Liver failure Hepatocellular carcinoma (HCC)

• The treatment– Viral cure, or sustained virologic response (SVR), is

achievableachievable– SVR associated with histologic improvement and

gradual regression of fibrosis1

– SVR leads to lower risk for liver failure and HCC, and improved survival2,3

1. Poynard T, et al. Gastroenterology 2002;122:1303-1313. 2. Craxi A, et al. Clin Liver Dis 2005;9:329-346. 3. Shiratori Y, et al. Ann Intern Med 2005;142:105-114.


2


Histologic Improvement After Successful Anti-HCV Therapy

Long-term, follow-up biopsy obtained from the same patient 57 months after end of treatment:Trichrome stain with Ishak stage 1 fibrosis

Pretreatment biopsy:Trichrome stain with Ishak stage 3 fibrosis(portal-to-portal bridging)

George S, et al. Hepatology 2009;49:729-738.

SVR Is Equivalent to Viral Cure


3


The Evolution of HCV Therapy

80

100

%)

1986 1998 2001 2002

70 75

2011-13

20

40

60

80

SV

R (

%

16

34

42 39

54-56

70-75

Modified from Strader DB, et al. Diagnosis, Management, and Treatment of Hepatitis C. Hepatology 2004;39:1147-1171.

0IFN6 mo

IFN/RBV6 mo

PEG-IFN /RBV12 mo

IFN12 mo

IFN/RBV12 mo

PEG-IFN12 mo

6

PEG-IFN /RBV + PI6-12 mo

Is Risk-Based HCV Screening the Best Approach?

• High HCV prevalence in “baby boomer” population (born 1946-1964) )

– HCV may have been acquired decades ago

– Individuals no longer identified as high risk

– Aging of population anticipated to yield ↑ advanced liver disease

• Study investigated impact of targeted “birth cohort screening”

– 1-time screening of all US persons born 1946-1964 vs risk-based screening through 70 yrs of age

– Utilized Markov model of natural history of HCV and liver disease, incorporating diagnosis and treatment, to estimate HCV-associated outcomes for both screening approaches

McGarry L, et al. Digestive Disease Week 2011. Abstract 477.


4


Birth Cohort vs Risk-Based HCV Screening

Outcome Estimate, n Birth Cohort Screening

Risk-BasedScreening

DifferenceScreening Screening

Total screened 78,700,000 8,000,000 +70,700,000

Diagnosed 1,312,391 427,030 +885,361

Treated 742,329 234,689 +507,640

SVR 404,274 124,650 +279,624

Decompensated cirrhosis

238,500 291,200 -52,700

HCC 137,400 166,000 -28,600

• Limitations of analysis: model is simplified view of disease and treatment; validity dependent on model assumptions; data combined from various sources; incident infection and transmission not included in model; new HCV treatments not considered

McGarry L, et al. Digestive Disease Week 2011. Abstract 477.

, , ,

Liver transplantation 28,700 34,700 -6000

HCV death 233,200 281,200 -48,000

Core E1 E2 P7

NS2 NS3 NS4A NS4B NS5A NS5B

Targets for New Hepatitis C Drugs

5′– –3′

Protease Polymerase

Linear TelaprevirBoceprevirACH-1625GS-9256

Macrocyclic Danoprevir (RG7227)TMC 435350BI-201335

BMS-790052

Active site (nucleosides)

RG7128IDX184PSI-7977

Non-nucleosides ABT-333ABT-072

Protease inhibitors

yinhibitorsClemizole

BMS-650032Vaniprevir

GS 9190ANA598VCH-759VCH-916VX-222FilibuvirBI-207127

Cyclophilin Debio 025SCY-635

Not all-inclusive


5


To Treat or not to Treat:

A Constellation of Considerations

Duration ofinfection

Genotype virusGenotype Patient (IL28)

Histologic stage20%+ lifetime risk

of cirrhosis

Personal plans(marriage,pregnancy)

Age

Patient

Family and othersupport

ALT

HIV coinfectionExtrahepatic

Features(Fatigue, EMC, PCT)

Patient"mindset"

Contraindications& comorbidities

Insulin Resistance

Occupation

PinK AALSD CME 2009

Boceprevir and Telaprevir Clinical Trials

• Phase III trials leading to approval

Boceprevir plus pegIFN/RBV– Boceprevir plus pegIFN/RBV

SPRINT-2: treatment-naive patients[1]

RESPOND-2: treatment-experienced patients[2]

– Telaprevir plus pegIFN/RBV

ADVANCE: treatment-naive patients[3]

ILLUMINATE: treatment-naive patients[4]ILLUMINATE: treatment naive patients

REALIZE: treatment-experienced patients[5]

1. Poordad F, et al. N Engl J Med 2011;364:1195-1206. 2. Bacon BR, et al. N Engl J Med 2011;364:1207-1217. 3. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 4. Sherman KE, et al. 2010 AASLD. Abstract LB2. 5. Zeuzem S, et al. N Engl J Med 2011;364:2417-2428.


6


SPRINT-2: Boceprevir in GT1 Treatment-Naive Patients

Wk 72Wk 48Wk 28Wk 4

Treatment-naive patients with

genotype 1 HCV

(2 cohorts: N = 938

PR*(n = 316,

52) Follow-up

Follow-up

BOC + PR*(n = 316 nonblack,

52 black)

BOC + PR*(n = 311 nonblack, 55 black)

PR*(n = 311,

55)

Detectable Wks 8-24:PR*

Undetectable Wks 8-24:Follow-up

nonblack and 159 black)

PR*(n = 311 nonblack, 52 black)

Follow-up

*BOC 800 mg q8h, pegIFN alfa-2b 1.5 µg/kg/wk, weight-based RBV 600-1400 mg/day.

Poordad F, et al. N Engl J Med 2011;364:1195-1206.

PR*(n = 311,

55)

Treatment With Boceprevir

• All patients initiate therapy with 4-wk pegIFN/RBV lead in phasepegIFN/RBV lead-in phase

• After completion of lead-in phase, boceprevir should be added to continued pegIFN/RBV

– Boceprevir: 800 mg TID, every 7-9 hrs

– Boceprevir should be administered with food (li ht k l)(light snack or meal)

Boceprevir [package insert]. May 2011. Boceprevir. European Medicines Agency.


7


SVR and Relapse Rates

P < .001 P = .004

SVR Relapse Rate

SPRINT-2: BOC + PegIFN/RBV in GT1 treatment-naïve patients

23

4253

1740

60

80

100

Per

cen

t

40

67 68

2340

60

80

100

Per

cen

t

P < .001P = .04

P .004

125311

211316

213311

2252

2955

14 12 17

0

20

48 P/R BOC RGTBOC/PR48P23

9 8

0

20

48 P/R BOC RGT BOC/PR48

P

Non-Black Patients Black Patients

311

1252

52

37162 21

23218

2302

143

25

635

Poordad F, et al. New Engl J Med. 2011;364:1195-1206.

SPRINT-2 Subanalysis: Response to 4-Wk PegIFN/RBV Lead-in

• Response to 4-wk lead-in phase with pegIFN/RBV strongest di t f SVR i lti i t l i (OR 9 0 P 001)predictor of SVR in multivariate analysis (OR: 9.0; P < .001)

– When 4-wk lead-in phase included as continuous variable, IL28Bgenotype no longer significantly predictive of SVR

81 79

60

80

100 < 1 log10 decline in HCV RNA

≥ 1 log10 decline in HCV RNA

%)

Poordad F, et al. EASL 2011. Abstract 12. Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

2838

4

51

0

20

40

60

BOC RGT BOC/PR48 PR48

SV

R (

%

27/97

203/252

36/95

200/254

3/83 133/

260n/N =


8


Boceprevir: Duration of Therapy for Noncirrhotic Treatment-Naive Patients

• HCV RNA levels at Wks 8, 12, and 24 used as decision pointspoints

– HCV RNA assay should have 25 IU/mL limit of quantification

Undetectable < 100 IU/mL Undetectable Complete 3-drug regimen at Wk 28

Detectable < 100 IU/mL Undetectable

1) Continue all 3 drugs through Wk 36, then

2) continue pegIFN/RBV through Wk 48

Detectable ≥ 100 IU/mL N/A Discontinue all 3 drugs at Wk 12

Boceprevir [package insert]. May 2011. Boceprevir. European Medicines Agency.

ADVANCE: Telaprevir + PegIFN/RBV in GT1 Treatment-Naive Patients

Wk 12 Wk 72Wk 48Wk 8 Wk 24

Treatment-naive patients withgenotype 1

HCV

TVR + PR*(n = 364)

TVR + PR*(n = 363)

eRVR†: PR* Follow-up

Follow-up

Follow-up

PR*

eRVR†: PR*

PR*

Follow-up

(N = 1088)

PR*(n = 361)

*TVR 750 mg q8h, pegIFN alfa-2a 180 µg/wk, weight-based RBV 1000-1200 mg/day.†eRVR: extended rapid virologic response = undetectable HCV RNA at Wks 4 and 12.

Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

Follow-up


9


Treatment With Telaprevir

• All patients initiate therapy with 12-wk period of p py ptriple therapy with telaprevir plus pegIFN/RBV

– Telaprevir: 750 mg TID, every 7-9 hrs

– Telaprevir should be administered with food (standard or high fat)

Standard fat meal would be 21 g such as 2Standard fat meal would be 21 g, such as 2 oz of cheese or 1/2 cup of nuts

Telaprevir [package insert]. 2011.

ADVANCE: Overall SVR and Relapse Rates

100 P 0001 f b h8-wk TVR/PR + 16/40-wk PR (n = 364)

40

60

80

100

Pat

ient

s (%

) 6975

44

P < .0001 for both treatment arms vs control

12-wk TVR/PR + 12/36-wk PR (n = 363)

48-wk PR (n = 361)

28

0

20

SVR

Jacobson IM, et al. AASLD 2010. Abstract 211. These data are available in unpresented abstract format only, and will be presented in full during the AASLD meeting. We encourage you to review the presented data before making conclusions.

n = 250 271 158

Relapse

9 9

28

n = 28 27 64


10


Response-Guided Approach With TVR in Tx-Naive Patients Supported

by 2 Studies• ADVANCE: suggested 24 wks of therapy sufficient for patients with eRVR

A ti t i T12PR48 h hi d RVR d i d 24 k– Among patients in T12PR48 arm who achieved an eRVR and received 24 wks therapy, SVR was 89%

8997

54

39VR

(%

)

40

60

80

100 T12PRPR

Jacobson IM, et al. N Engl J Med 2011;364:2405-2416.

eRVR Positive(TVR patients

treated for 24 wks)

eRVR Negative(All treated for 48 wks)

SV

0

20

40

189/212

28/29

130/332

82/151n/N =

Response-Guided Approach With TVR in Tx-Naive Patients Supported by 2

Studies• Robustness of response-guided therapy confirmed by ILLUMINATE

– 92% of those who received 24 wks of total therapy following eRVRachieved SVR

100

80

60

R (

%)

∆ 4.5%(2-sided 95% CI: -2.1% to +11.1%)

72

9288

64

eRVR + T12PR24

Sherman K, et al. AASLD 2010. Abstract LB2.

40

20

0

SV

R

ITT eRVR + T12PR48

eRVR + T12PR48

Other

23


11


Telaprevir: Duration of Therapy for Treatment-Naive Patients

• After 12 wks, telaprevir should be discontinued and pegIFN/RBV continued

– Cirrhotic patients with undetectable HCV RNA at Wks 4 and 12 may nevertheless benefit from additional 36 wks of pegIFN/RBV (48 wks total) rather than response-guided therapy

Response-Guided Therapy

HCV RNA Triple Therapy:TVR + PegIFN/RBV

Dual Therapy: PegIFN/RBV

Total Treatment Duration

Undetectable at Wks 4 and 12 First 12 wks Additional 12 wks 24 wks

Detectable (but ≤ 1000 IU/mL) at Wks 4 and/or 12

First 12 wks Additional 36 wks 48 wksat Wks 4 and/or 12

Stopping Rules

Time Point Criteria Action

Wk 4 or 12 HCV RNA > 1000 IU/mL Discontinue all therapy

Wk 24 HCV RNA detectable Discontinue pegIFN/RBV

Any Discontinuation of pegIFN/RBV for any reason Discontinue TVR

Telaprevir [package insert]. 2011.

Retreatment With BOC + PegIFN/RBV in Treatment-Experienced Patients

100

Previous relapse

40

60

80

40

69

52

75

VR

(%

)[3]

Previous partial response

1. Boceprevir [package insert]. 2011. 2. Ghany MG, et al. Hepatology 2011;54:1433-1444. 3. Bacon BR, et al. N Engl J Med 2011;364:1207-1217.

0

20

BOC RGT BOC/PR48

7

29

PR48

n/N = 2/29 15/51 23/57 72/105 30/58 77/103

SV


12


SVR in Previous Relapsers, Partial Responders, Null Responders

REALIZE: TVR + PegIFN/RBV in G1 Previous Relapsers and Partial/Null Responders

100

60

R (

%)

80

Previous Relapsers Previous Partial Responders

Previous Null Responders

83*88*

59*54*

T12/PR48PR48 LI T12/PR48

0

SV

R

40

n/N=

*P < .001 vs PR48.

20

121/145 124/14116/68

24

29/49 26/484/27

15

21/72 25/75

29*33*

2/37

5

Zeuzem S, et al. N Engl J Med 2011;364:2417-2428.

SVR in Poorly IFN-Responsive Patients by Wk 4 PR Lead-in Response

RESPOND-2: BOC + PegIFN/RBV in GT 1 Treatment-Experienced Patients

VR

(%

)

100

80

60

VR

(%

)

100

80

60

7379

Poorly Responsive to IFN:< 1 log10 HCV RNA decline at Wk 4

Responsive to IFN:≥ 1 log10 HCV RNA decline at Wk 4

0/12

15/46

15/44

SV

PR48

40

20

0

0

33 34

BOC RGT BOC/PR48

17/67

80/110

90/114

SV

PR48

40

20

0

25

BOC RGT BOC/PR48

n/N =

Bacon BR, et al. N Engl J Med 2011;364:1207-1217.


13


SVR in Poor IFN Responders Based on TW8 Response (Log Decline in VL Compared to BL VL) (BOC

Arms Combined)

91

7983

80

100

38

21

50

9

33

48

16

30

49

20

40

60

80

%

SV

R

0 0 00

RESPOND-2 SPRINT-2 CombinedStudies

<3 3-4 4-5 >5

016

38

628

1020

1011

028

223

2370

1531

2329

<3 3-4 4-5 >5 <3 3-4 4-5 >5

044

531

2998

2551

3340

Efficacy of boceprevir in prior null responders to peginterferon/ribavirin: the PROVIDE study*

100 PEG IFNα 2b : 1 5 µg/kg/week + ribavirin 600 1400 mg/day+

473840

60

80

100

Pat

ien

ts (

%)

PEG-IFNα-2b : 1,5 µg/kg/week + ribavirin 600-1400 mg/day+ boceprevir 800 mg day

16

0

20

n/N =

EOT20/43

SVR16/42

Relapse3/19

*Of 48 prior null responders from SPRINT-2 and RESPOND-2, 3 discontinued during the 4-week lead-in phase, 2 are ongoing treatment(1 entering TW3, 1 entering TW18 of BOC/PR) and 1 is in follow-up phase Relapse: an undetectable HCV RNA level at EOT, but with a detectable HCV RNA level during the follow-up period

Vierling J, et al. Hepatology 2011;54(Suppl. S1): Abstract 931


14


Prior relapsers

Prior partial responders

Prior null responders

87100 Pbo/PR48

Telaprevir in Patients With Bridging Fibrosis or Cirrhosis

32

18 20

87 85 8477

56

3441 39

40

60

80Pooled T12/PR48

SV

R (

%)

137

18

06

0

1014

0

20

53/62n/N= 2/1512/38 145/167 10/180/53/17 36/47 16/380/91/5 11/32

No, minimal or portal fibrosis

CirrhosisStage

48/571/15 1/18 24/59 1/10 7/50

Bridgingfibrosis


CirrhosisBridgingfibrosis


CirrhosisBridgingfibrosis

http://www.fda.gov/downloads/AdvisoryCommittees/Committees/MeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf

SVR was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used

Key for Waves of New Ggents:Direct-Acting Anti-Virals (DAAs) and Host-Targeting antiviral (HTAs)

First Wave Second Wave Third Wave

DAAs1st 2nd 3rd

Telaprevir Boceprevir

TMC435BI 201335BMS-790052PSI-7977

BI 201335/BI 207127BMS-790052/BMS-650032Mericitabine/MK-5172

Alisporivir/DEB 025 SCY635

HTAs

30


15


HCV Pipeline by Mechanism of Action and Stage of Development

*Only represents a sample of agents in development for HCVSchlutter J. Nature. 2011;474(7350):S5-S7.© 2011 Nature Publishing Group.

Antiviral Efficacy of 2nd Wave NS3 PIs

4

5

0IU

/mL

)

3.8 3.94.2

4.6

1

2

3

HC

V R

NA

Dec

line

(lo

g10

3.3

1.8

0

1

Danoprevir200 mg TID

TMC435200 mg QD

BI-201335 240 mg QD

Vaniprevir700 mg BID

BMS-650032 400

mg BID

PHX1766 800 mg BID

Mea

n

Sarrazin C, Zeuzem S. Gastroenterology. 2010;138(2): 447-462. © 2010 by the AGA Institute.


16


Goals for Hepatitis C Therapy

• Compared to PegIFN/RBV, new products should offer:offer:– Improved efficacy

– Efficacy in all patient types including previously treated patients, cirrhotic and black patients

– Orally effective regimen, IFN free

– Shorter treatment duration

– Improved side-effect profile

Selected Oral Directing Acting Antivirals for the Treatment of Chronic Hepatitis C, 2012

Compound Sponsor Activity

ABT 267 Abbott NS5A inhibitorABT-267 Abbott NS5A inhibitor

ABT-333 Abbott Non-nucleoside NS5B polymerase inhibitor

ABT-450 Abbott NS3/4A protease inhibitor

Faldaprevir Boehringer Ingelheim NS3/4A proteaseFaldaprevir(BI201335)

Boehringer Ingelheim NS3/4A protease inhibitor

BI207127 Boehringer Ingelheim Non-nucleoside NS5B polymerase inhibitor


17


Selected Oral Directing Acting Antivirals for the Treatment of Chronic Hepatitis C, 2012 (cont)

Compound Sponsor ActivityAsunaprevir Bristol-Myers Squibb NS3 protease inhibitorp

(BMS-650032) y q p

Daclatasvir(BMS-790052)

Bristol-Myers Squibb NS5A replication complex inhibitor

BMS-791325 Bristol-Myers Squibb Non-nucleoside NS5B polymerase inhibitor

Sofosbuvir(GS 7977)

Gilead Uridine nucleotide analog NS5B(GS-7977) analog NS5B polymerase inhibitor

GS-5885 Gilead NS5A protein inhibitor

Not all-inclusive, but indicates drugs covered in this presentation

• Five arm study that evaluated different doses and durations in regimens with

SOUND-C2 Trial Update: BI 201335 + BI 207127 ± RBV

faldaprevir (PI) and BI207127 (non-nuc) with or without RBV

– Durations: 16, 28 or 40 weeks

– BID vs TID

• Randomization was stratified by genotype (1a vs 1b) and IL28B

– 9% of patients had cirrhosis

• SVR12 ranged between 52% to 69% in RBV-containing arms and 39% without RBV

SVR i i h ti i 54%*

Zeuzem S et al. Hepatology 2012; 56(Suppl S1):308A-309A; *Soriano V et al, Abstract 84, AASLD 2012

– SVR in cirrhotics is 54%*

• IL28B CC, genotype 1b and female gender were favorably associated with SVR12


18


SOUND-C2 Trial Update: Faldaprevir + BI 207127 ± RBV

Primary endpoint: SVR12 (ITT and per protocol)

100

40

60

80

SVR12(%)

66% 69% 69% 72%

44%59% 59%

52%

69%

39%

ITT

Per Protocol

Zeuzem S et al. Hepatology 2012; 56(Suppl S1):308A-309A.

0

20

BI 207127 Dosing TID TID TID BID TID

Duration (weeks) 16 28 40 28 28

RBV + + + + ‒

ELECTRON Trial

Objective• To evaluate sofosbuvir (SOF; formerly GS-7977), a uridine

nucleotide analog, plus ribavirin (RBV) in additional g, p ( )ELECTRON study arms:• SOF + RBV in treatment-naïve genotype 1 patients• SOF + RBV in null responder genotype 1 patients• SOF + RBV in treatment experienced (Prior null

response, breakthrough, or relapse) in genotype 2/3 patients

• To determine feasibility of shorter duration or reducedTo determine feasibility of shorter duration or reduced dose of RBV in treatment naive genotype 2/3 patients

• To evaluate the efficacy and safety of adding GS-5885, an NS5A inhibitor, to SOF + RBV in treatment naïve and null responder genotype 1 patients

Gane EJ et al. Hepatology 2012; 56(Suppl S1):306A-307APress release. November 10, 2012. Gilead Sciences, Inc., Foster City, CA. Available at http://www.gilead.com/pr_1757156.


19


ELECTRON Trial Update: Sofosbuvir + RBV vs.

Sofosbuvir + GS-5885 + RBV in Genotype 1 HCV

SOF + RBV SOF + GS-5885 + RBV

T t t N ll T t t N ll

Adverse Events, n (%)

Treatment-Naïve (n=25)

Null Responder

(n=10)

Treatment-Naïve (n=25)

Null Responder

(n=9)

SAEs* 1 (4) 0 2 (8) 0

AEs that led to discontinuation

0 0 1 (4) 0

≥Grade 2 AEs 10 (40) 3 (30) 12 (48) 2 (22)

A i 0 1 (10) 5 (20) 0

*SAEs considered unrelated to SOFStopped treatment at week 8 at time of partial colectomy for diverticular perforation

Gane EJ et al. Hepatology 2012;56(Suppl S1):306A-307A

Anemia 0 1 (10) 5 (20) 0

Headache 1 (4) 0 1 (4) 0

Depression 0 1 (10) 2 (8) 0

Ligament sprain 1 (4) 1 (10) 0 0

ELECTRON Trial Summary: Genotype 1 HCV

• SOF + RBV for 12 weeks provided SVR12 in 84% of treatment-naïve, but only in 10% of null responders

• Addition of GS-5885 increased efficacy of SOF + RBV

– 100% SVR4 in treatment-naïve patients

Gane EJ et al. Hepatology 2012;56(Suppl S1):306A-307A

– 3/3 SVR4 in null responders

– No additional safety/tolerability issues detected


20


SOF in Combination with Low or Full Dose RBV in Difficult to Treat

Genotype 1 HCV Patients

Objective:Objective:

• To assess the safety, tolerability, and efficacy of SOF in combination with weight-based (full) or low dose ribavirin (RBV) for 24 weeks in HCV mono-infected, genotype 1, treatment-naive subjectsj

• SOF is a specific nucleotide analog HCV polymerase inhibitor

Osinusi A et al. Abstract LB-4. Presented at The Liver Meeting® 2012, Boston, MA, November 9-13, 2012

SOF in Combination with Low or Full Dose RBV in Difficult to Treat Genotype

1 HCV PatientsTreatment Response: Full dose RBV (Part 1; N=10)

100 90% 90% 90% 90% 90%

40

60

80

100

ITTHCV RNA

<LLOQ(%)


0

20

Week 4 Week 12 ETR SVR4 SVR12

• mITT: 100% SVR12 (1 drop out at week 3)


21


SOF in Combination with Low or Full Dose RBV in Difficult to Treat Genotype

1 HCV Patients

Conclusions:

• In this inner city population of HCV genotype 1 treatment-naïve patients, SOF + RBV administered for 24 weeks resulted in:

– Full dose RBV: SVR4 of 77%

– Low dose RBV: SVR4 of 56%


– Low dose RBV: SVR4 of 56%

• There were no safety signals or drug-related discontinuations in this study

All-Oral Combination of Daclatasvir Plus Sofosbuvir ± Ribavirin in

Treatment Naïve HCV GT 1, 2, or 3Objective:j

• To evaluate the efficacy and safety of daclatasvir (DCV; BMS-790052) plus sofosbuvir (SOF; GS-7977) with or without RBV

– 24 weeks in treatment-naïve patients infected with HCV GT1 (1a/1b), 2, or 3

12 weeks in treatment naïve patients infected with– 12 weeks in treatment-naïve patients infected with GT1 (1a/1b)

• DCV is an NS5A replication complex inhibitor; SOF is a nucleotide analogue NS5B polymerase inhibitor

Sulkowski MS et al. Abstract LB-2. Presented at The Liver Meeting® 2012, Boston, MA, November 9-13, 2012


22


Virologic Response is Maintained at PT Week 24 (GT 2 or 3; 24-Week

Treatment Groups)

120SOF LI + DCV DCV + SOF DCV + SOF + RBV

10094

88 88 88100 100 100 100 100100 100

86 8693

40

60

80

100

120

HCV RNA<LLOQ

(% patients)


0

20

Week 4 EOT SVR4 SVR12 SVR24

16 14 14 16 14 14 16 14 14 16 14 14 16 14 14

All-Oral Combination of DaclatasvirPlus Sofosbuvir ± Ribavirin in

Treatment Naïve HCV GT 1, 2, or 3

Conclusions:

• DCV + SOF with or without RBV achieved SVR in ≥93% of patients with HCV genotype 1, 2, or 3

• HCV genotype 2 or 3 (N=44)

– 24-week duration: SVR24=93% of patients

• HCV genotype 1 (N=126)


g yp ( )

– 12-week duration: SVR4=96%

– 24-week duration: SVR24=98%


23


ABT-450/r, ABT-267, ABT-333 and RBV in Treatment Naïve and Prior Null Responders with Genotype 1 HCV

Objectivej

• To assess efficacy and safety of several interferon free regimens of ABT-450/r with ABT-267 and/or ABT-333 ±ribavirin (RBV)

– ABT-450 is an HCV NS3/4 protease inhibitor that is co-administered with ritonavir (ABT-450/r) and dosed once dailyonce daily

– ABT-267 is an NS5A inhibitor that is dosed once daily

– ABT-333 is a non-nucleoside polymerase inhibitor dosed twice daily

Kowdley KV et al. Abstract LB-1. Presented at The Liver Meeting® 2012, Boston, MA, November 9-13, 2012

ABT-450/r, ABT-267, ABT-333 and RBV in Treatment Naïve and Prior Null

Responders with Genotype 1 HCV

87.5% 85.4% 89.9% 87.3%97.5%

88.9% 93.3%100SVR12 Rates (ITT) for 8- and 12-week Arms

85.4%

20

40

60

80

ITTSVR12

(%)

n=80 n=79 n=79 n=79 n=45 n=45n=41


0ABT-450

ABT-333RBV

ABT-450ABT-267

RBV

ABT-450ABT-267ABT-333


RBV


RBV

ABT-450ABT-267

RBV


RBV

8 wks 12 wks 12 wks

Treatment Naïve Prior Null Responder

n 80


24


ABT-450/r, ABT-267, ABT-333 and RBV in Treatment Naïve and Prior Null

Responders with Genotype 1 HCVConclusionsCo c us o s

• The 12-week 3 DAA + RBV regimens showed the greatest efficacy in both treatment-naive and null responder populations

• All DAA combinations studied were well tolerated through 8 - 12 weeks of treatment


• Phase 3 studies with the 3 DAA combination (with and without RBV) recently initiated

What’s In the Future? – Multiple DAAs?

Multiple DAAs + IFN Backbone + RBV• 2nd generation PIs• Nucleoside polymerase inhibitors• NS5A inhibitors• Nonnucleoside polymerase inhibitors (NNIs)

• Considerations:Considerations:– 2 DAA programs– Consider replacing RBV– RGT


25


What’s In the Future? – IFN Free?

Polymerase BackbonePolymerase Backbone

• Highest resistance barrier

• Pan-genotypic

• Second generation PI / NS5A / NNI / RBV

• Cyclophilin inhibitor

• 3- or 4-drug regimens

• SVR?

Antiviral activity in all HCV genotypesAntiviral activity in all HCV genotypes No selection of resistanceNo selection of resistance

HCV — The Revolution Has Begun

All-oral combination regimenAll-oral combination regimen Short treatment durationShort treatment duration

QD (or BID) dosingQD (or BID) dosing Excellent safety and tolerabilityExcellent safety and tolerability

Applicable in difficult-to-treat populations: Transplant Coinfection End-stage renal disease, etc.

Applicable in difficult-to-treat populations: Transplant Coinfection End-stage renal disease, etc.


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